Angiotensin converting-enzyme inhibitor treatment reduces glomerular p16(INK4) and p27(Kip1) expression in diabetic BBdp rats

Aims/hypothesis. Renal hypertrophy occurs early in diabetes mellitus and pr ecedes the development of glomerulosclerosis and tubulointerstitial fibrosi s. We have previously shown that cultured mesangial cells exposed to high g lucose are arrested in the G(1)-phase of the cell cycle and undergo cellula r hypertrophy. High glucose-mediated induction of p27(Kip1), an inhibitor o f cyclin-dependent kinases, is essential in this process. Further investiga tions have also shown that p27(Kip1) and p21(Cip1), other cyclin-dependent kinase inhibitors, are up regulated in the kidneys of mice with Type I (ins ulin-dependent) as well as Type II (non-insulin-dependent) diabetes mellitu s. Our study was undertaken to test a potential effect of short-term treatm ent with the angiotensin-converting enzyme inhibitor enalapril on the glome rular expression of the cyclin-dependent kinase inhibitors p16(INK4), p21(C ip1) and p27(Kip1) in BBdp rats, an autoimmune model of Type I diabetes. Methods. We evaluated p16(INK4), p21(Cip1), and p27(Kip1) protein expressio n in isolated glomeruli by western blots. We also assessed p27(Kip1) positi ve glomerular cells by immunohistochemistry. Results. Glomerular expression of all three cyclin-dependent kinase inhibit ors were stimulated in BBdp rats compared with non-diabetic BBdr animals. E nalapril treatment for 3 weeks, started after the onset of diabetes, reduce d the glomerular expression of p16(INK4) and p27(Kip1) but not of p21(Cip1) . Enalapril also prevented the increase in kidney weights observed in BBdp rats but had no effect on systolic blood pressure or glucose concentrations . Conclusion/interpretation. Our data show that enalapril attenuates the glom erular expression of cyclin-dependent kinase inhibitors in diabetes and sug gest a molecular mechanism of how angiotensin-converting enzyme inhibitors prevent renal hypertrophy in diabetes.